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The FASEB Journal

Research Communication

D-cycloserine improves functional recovery and reinstates long-term potentiation (LTP) in a mouse model of closed head injury

R a m i Y a k a , * , 1 A n a t B i e g o n , N i k o l a o s G r i g o r i a d i s , C o n s t a n t i n a S i m e o n i d o u , § S a v v a s G r i g o r i a d i s , A l e x a n d e r G . A l e x a n d r o v i c h , * H e n r i M a t z n e r , * J o h a n n a S c h u m a n n , * V i c t o r i a T r e m b o v l e r , * J e a n n a T s e n t e r , * , and Esther Shohami*

* D e p a r t m e n t o f P h a r m a c o l o g y , S c h o o l o f P h a r m a c y , H e b r e w U n i v e r s i t y , J e r u s a l e m , I s r a e l ; B r o o k h a v e n N a t i o n a l L a b o r a t o r y , U p t o n , N e w Y o r k , U S A ; D e p a r t m e n t o f N e u r o l o g y , A H E P A U n i v e r s i t y H o s p i t a l , G r e e c e ; § D e p a r t m e n t o f P h y s i o l o g y , F a c u l t y o f M e d i c i n e , A r i s t o t l e U n i v e r s i t y o f T h e s s a l o n i k i , G r e e c e ; D e p a r t m e n t o f N e u r o s u r g e r y , H a d a s s a h U n i v e r s i t y H o s p i t a l , J e r u s a l e m , I s r a e l ; a n d D e p a r t m e n t o f R e h a b i l i t a t i o n , H a d a s s a h M e d i c a l C e n t e r , J e r u s a l e m , I s r a e l


Traumatic brain injury triggers a massive

glutamate efflux, activation of NMDA receptor chan- nels, and cell death. Recently, we reported that NMDA receptors in mice are down-regulated from hours to days following closed head injury (CHI), and treatment with NMDA improved recovery of motor and cognitive functions up to 14 d post-injury. Here we show that a single injection of a low dose of D-cycloserine (DCS), a partial NMDA receptor agonist, in CHI mice 24 h post-injury, resulted in a faster and greater recovery of motor and memory functions as assessed by neurolog- ical severity score and object recognition tests, respec- tively. Moreover, DCS treatment of CHI mice led to a significant improvement of hippocampal long-term po- tentiation (LTP) in the CA1 region that was completely blunted in CHI control mice. However, DCS did not improve CHI-induced impairment in synaptic gluta- mate release measured by paired pulse facilitation (PPF) ratio in hippocampal CA1 region. Finally, CHI- induced reduction of brain-derived neurotrophic factor (BDNF) was fully restored following DCS treatment. Since DCS is in clinical use for other indications, the present study offers a novel approach to treat human brain injury.—Yaka, R., Biegon, A., Grigoriadis, N., Simeonidou, C., Grigoriadis, S., Alexandrovich, A. G., Matzner, H., Schumann, J., Trembovler, V., Tsenter, J., Shohami, E. D-cycloserine improves functional recov- ery and reinstates long-term potentiation (LTP) in a mouse model of closed head injury. FASEB J. 21,

2033–2041 (2007)

Key Words: traumatic brain injury NMDA receptors synap- tic plasticity BDNF

sient increase in glutamate efflux in the brain of experimental animals as well as humans (2–7). A key role for glutamate activity has been ascribed to the glutamate- gated N-methyl-D-aspartate receptors (NMDAR) ion (cal- cium) channel. When glutamate binds at the extracellular side of the receptor along with glycine, binding as a cofactor, the channel is opened, leading to calcium influx into the cell. Excessive glutamate release in the brain (8–10) is implicated in excitotoxic neuronal death following brain ischemia and trauma, and nu- merous studies show that competitive or noncompeti- tive inhibitors of NMDAR improved outcome in animal models of TBI and stroke (10–12). Thus, it has long been thought that hyperactivation of NMDAR under- lies cognitive and neurological decline after head in- jury. However, the NMDAR antagonists appeared to be beneficial only within a fairly narrow therapeutic win- dow, such that treatment initiation more than 30 min after injury was no longer protective (10–12).

It is generally believed that activity-dependent synap- tic processes that modify the strength of hippocampal glutamatergic synapses, known as long-term potentia- tion (LTP) and long-term depression (LTD), are criti- cal for spatial learning and memory (13). Such pro- cesses are the means by which the hippocampus can regulate the storage of information and require activa- tion of NMDARs (14). TBI produces chronic cognitive learning/memory deficits that are thought to be medi- ated, in part, by impaired hippocampal function. Ex- perimental TBI results in a chronic inability of the hippocampal CA1 neurons to maintain synaptic plastic- ity and LTP (15–18), and a significant amelioration of LTP impairment was demonstrated after treatment with cyclosporine A (19). It is, therefore, suggested that

Traumatic brain injury (TBI) is a leading cause of mortality and morbidity among young people in the western world (1). Yet, to date, no pharmacological agent has been approved to treat TBI patients. Trau- matic and ischemic brain injury triggers a large, tran-

1 Correspondence: Department of Pharmacology, School of Pharmacy, The Hebrew University of Jerusalem, POB 12065, Jerusalem 91120, Israel. E-mail: yaka@md.huji.ac.il

doi: 10.1096/fj.06-7856com

0892-6638/07/0021-2033 © FASEB


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